Melanogenesis inhibitor and skin preparation containing the same

ABSTRACT

A melanogenesis inhibitor characterized by containing at least one kind of piperonyl alcohol represented by the following general formula (1) 
                         
wherein R is a straight chain or branched chain alkyl group having 3 to 18 carbon atoms, a straight chain or branched chain alkenyl group having 3 to 18 carbon atoms, or an optionally substituted alicyclic alkyl group.
 
     The melanogenesis inhibitor is superior in stability and safety and has a high melanogenesis-inhibiting effect; and a skin preparation containing the melanogenesis inhibitor is very stable, safe, and has a sufficient fair skin effect and a sufficient effect for curing skin dyspigmentation.

This application is a 371 of international applicationPCT/JP2004/001496,which claims priority based on Japanese patentapplication No. 2003-036011 filed Feb. 14, 2003 ,which is incorporatedherein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a novel melanogenesis inhibitorcontaining a piperonyl alcohol derivative and a skin preparationcontaining the novel melanogenesis inhibitor. The present inventionfurther relates to a novel piperonyl alcohol derivative which isincluded in the above piperonyl alcohol derivative and which is usefulas a component of the novel melanogenesis inhibitor.

2. Description of the Prior Art

Chloasmata, Hatchinson's freckles and skin pigmentation increase andbecome difficult to remove with aging, and are a large worryparticularly to persons of middle or advanced age. The mechanism ofcrisis of these dyspigmentations is still unknown in many respects;however, they are considered to appear because the melanogenesisfunction at epidermal melanocytes is activated by the action of sunlight(ultraviolet light) or hormones. Inhibition of such melanogenesis ordecoloration of generated melanin is a task in development of fair skinpreparation or fair skin cosmetic, and various researches have beenmade.

In fair skin cosmetics for prevention or treatment of chloasmata,Hatchinson's freckles, etc. of skin, there have been compoundedL-ascorbic acid and its derivatives, hydroquinone and its derivatives,pyrones (e.g. kojic acid), placenta extract (see, for example, patentliterature 3), etc., all of which are well known to have, for example,an effect of melanogenesis inhibition due to hindrance of tyrosinaseactivity (see, for example, patent literatures 1 and 2) or an effect ofdecoloration of generated melanin and further have a fair skin effect.

When the above substances are used singly, however, there are variousproblems. For example, L-ascorbic acid and its derivatives areinsufficient in storage stability and do not exhibit the intended effectsufficiently; hydroquinone and its derivatives have a problem in safety(stimulativeness and allergenicity); kojic acid lacks in storagestability (easy to cause coloring); and placenta extract is slow to showits effect. Thus, each substance has been insufficient. Moreover, theireffects of melanogenesis inhibition are insufficient. Hence, developmentof a compound having a higher inhibition effect has been desired.

Patent literature 1: JP-A-10-29928

Patent literature 2: JP-A-8-119848

Patent literature 3: JP-A-8-104616

The present invention aims at providing a melanogenesis inhibitor whichis superior in stability and safety, which has a highmelanogenesis-inhibiting effect, and which, when made into a skinpreparation, is very stable, safe, and has a sufficient fair skin effectand a sufficient effect for curing skin dyspigmentation.

In such a situation, the present inventors made an intensive study onvarious compounds. As a result, it was found out that the above aim canbe achieved by a piperonyl alcohol derivative represented by thefollowing general formula (1)

wherein R is a straight chain or branched chain alkyl group having 3 to18 carbon atoms, a straight chain or branched chain alkenyl group having3 to 18 carbon atoms, or an optionally substituted alicyclic alkylgroup.

That is, the present inventors found out that the piperonyl alcoholderivative represented by the above general formula (1) is superior instability and safety and has a high melanogenesis-inhibiting effect andthat a skin preparation containing the derivative is very stable, safe,and has an excellent fair skin effect and an excellent effect for curingskin dyspigmentation. By a further study, it was made clear that themelanogenesis-inhibiting effect of the present invention compound isexpressed not by the tyrosinase activity-hindering effect (possessed byconventional compounds) but by a tyrosinase biosynthesis-hinderingeffect. The present invention has been completed based on the abovefinding.

SUMMARY OF THE INVENTION

The present invention includes the following inventions.

(1) A melanogenesis inhibitor characterized by containing at least onekind of piperonyl alcohol represented by the following general formula(1)

wherein R is a straight chain or branched chain alkyl group having 3 to18 carbon atoms, a straight chain or branched chain alkenyl group having3 to 18 carbon atoms, or an optionally substituted alicyclic alkylgroup.(2) A melanogenesis inhibitor according to (1), wherein the R in thegeneral formula (1) is an alicyclic alkyl group derived from a cyclicmonoterpene alcohol.(3) A skin preparation characterized by containing a melanogenesisinhibitor set forth in (1).(4) A skin preparation characterized by containing 0.001 to 20.0% bymass of a melanogenesis inhibitor set forth in (1).(5) A skin preparation according to (3) or (4), which has a form ofcream, lotion, emulsion, jelly, beauty lotion, pack or ointment.(6) A piperonyl alcohol derivative characterized by represented by thefollowing general formula (2)

wherein R′ is an alicyclic alkyl group derived from a cyclic monoterpenealcohol.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is described in detail below.

In the general formula (1) representing the piperonyl alcohol derivativecontained in the melanogenesis inhibitor of the present invention, R isa straight chain or branched chain alkyl group having 3 to 18 carbonatoms, a straight chain or branched chain alkenyl group having 3to 18carbon atoms, or an optionally substituted alicyclic alkyl group.

As specific examples of R when R is a straight chain or branched chainalkyl group having 3 to 18 carbon atoms, there can be mentioned straightchain alkyl groups such as n-propyl group, n-butyl group, n-hexyl group,n-octyl group, n-nonyl group, n-decyl group, n-undecyl group, n-dodecylgroup, n-tetradecyl group, n-pentadecyl group, hexadecyl group,octadecyl group and the like; and branched chain alkyl groups such asisopropyl group, isobutyl group, sec-butyl group, tert-butyl group,4-methylpentyl group, 5-methylhexyl group, 2-ethylhexyl group,6-methylheptyl group, 7-methyloctyl group, 8-methylnonyl group, 2,6-dimethylheptyl group, 3,7-dimethyloctyl gorup, 3,7,11-trimethyldodecylgroup and the like. However, the specific examples are not restrictedthereto.

As specific examples of R when R is a straight chain or branched chainalkenyl group having 3 to 18 carbon atoms, there can be mentionedstraight chain alkenyl groups such as allyl group, 1-propenyl group,1-butenyl group, 2-butenyl group, 3-butenyl group, 4-pentenyl group,5hexenyl group, 6-heptenyl group, 7-octenyl group, 8-nonenyl group,9-decenyl group, 1-pentenyl group, 1-hexenyl group, 1-heptenyl group,1-octenyl group, 1-nonenyl group, 1-decenyl group, 9-octadecenyl groupand the like; and branched chain alkenyl groups such as isopropenylgroup, 2-methyl-1-propenyl group, 3-methyl-2-butenyl group,4-methyl-3-pentenyl group, 5-methyl-4-hexenyl group, 6-methyl-5-heptenylgroup, 7-methyl-6-octenyl group, 8-methyl-7-noneyl group, 1-methyl1-propenyl group, l-methyl-l-butenyl group, l-methyl-1-pentenyl group,1-methyl-1-hexenyl group, 1-methyl-l-heptenyl group, 1-methyl-1-octenylgroup, 1-methyl-1-nonenyl group, 2,6-dimethyl-5-hetenyl group,2,6-dimethyl-1-heptenyl group, 3,7-dimethyl-2,6-octadienyl (geranyl,neryl) group, 3,7,11trimethyl-2,6,10-dodecatrienyl (farnesyl) group,3,7,11trimethyl-6,10-dodecadienyl (dihydrofarnesyl) group and the like.However, the specific examples are not restricted thereto.

As specific examples of R when R is an optionally substituted alicyclicalkyl group, there can be mentioned cyclopentyl group, cyclohexyl groupand cycloheptyl group with cyclohexyl group being preferred. However,the specific examples are not restricted thereto.

As specific examples of R when R is an optionally subtituted alicyclicalkyl group, there can be mentioned cyclopentyl group, cyclohexyl groupand cycloheptyl group with cyclohexyl group being preferred. However,the specific examples are not restricted thereto.

As specific examples of the optionally substituted alicyclic alkylgroup, there can be mentioned cyclohexyl group, cyclohexylmethyl group,cyclohexylethyl group, 4-isopropylcyclohexyl group,4-tert-butylcyclohexyl group, 2,4-dimethyl-3-cyclohexenyl group,2-tert-butylcyclohexyl group, 4-isopropylcyclohexylmethyl group,5-methyl-2-(1-methylethenyl) cyclohexyl group (isopulegyl),5-methyl-2-isopropylcyclohexyl group (p-menthan-3-yl, menthyl),1-methyl, 4-isopropylcyclohexenyl group (terpinenyl),1-methyl-4-isopropylcyclohexyl group (dihydroterpinenyl),1-methyl-4-isopropenyl-6-cyclohexen-2-yl group (carvenyl),6-methyl-3-isopropenylcyclohexenyl group (dihydrocarvenyl),1-(4-isopropenyl)cyclohexyl)methyl group (perillyl),4-methyl-1-isopropylbicyclo [3.1.0]hexan-4-yl group (4-thujanyl),4-methyl-1-isopropylbicyclo[3.1.0]hexan-3-yl group (3-thujanyl),6,6-dimethylbicyclo[3.1.1]hept-2-en-2-ethyl group (nopyl),1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl group (fenchonyl) andendo-1,7,7-trimethylbicyclo [2.2.1]heptan-2-yl group (bornyl).

As specific examples of the optionally substituted alicyclic alkylgroup, preferred are alicyclic alkyl groups each derived from a cyclicmonoterpene alcohol, such as 4-isopropylcyclohexylmethyl gorup,5-methyl-2-(1-methylethenyl cyclohexyl group (isopulegyl),5-methyl-2-isopropylcyclohexyl group (p-menthan-3-yl, menthyl),1-methyl-4-isopropylcyclohexenyl group (terpinenyl),1-methyl-4-isopropylcyclohexyl group (dihydroterpinenyl),1-methyl-4-isopropenyl-6-cyclohexen-2-yl group (carvenyl),6-methyl-3-isopropenylcyclohexenyl group (dihydrocarvenyl),1-(4-isopropenyl)cyclohexyl)methyl group (perillyl),4-methyl-1-isopropylbicyclo[3.1.0]hexan-4-yl group (4-thujanyl),4-methyl-1-isopropylbicyclo[3.1.0]hexan-3-yl group (3-thujanyl),6,6-dimethylbicyclo[3.1.1]hept-2-en-2-ethyl group (nopyl),1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl group (fenchonyl) andendo-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl group (bornyl).Particularly preferred is 5-methyl-2-isopropylcyclohexyl(p-menthan-3-yl, menthyl) group from the standpoint of safety,solubility and effect of the piperonyl alcohol derivative represented bythe general formula (1).

Therefore, as specific examples of the piperonyl alcohol represented bythe general formula (1), there can be mentioned, when R of the generalformula (1) is a straight chain or branched chain alkyl group having 3to 18 carbon atoms or a straight chain or branched chain alkenyl grouphaving 3 to 18 carbon atoms, 3,4-methylenedioxybenzyl n-propyl ether(piperonyl n-propyl ether), 3,4-methylenedioxybenzyl n-butyl ether(piperonyl n-butyl ether), 3,4-methylenedioxybenzyl n-hexyl ether(piperonyl n-hexyl ether), 3,4-methylenedioxybenzyl 2-ethylhexyl ether(piperonyl 2-ethylhexyl ether), 3,4-methylenedioxybenzyl3,7-dimethyl-2,6-octadienyl ether (piperonyl geranyl ether),3,4-methylenedioxybenzyl 3,7,11-trimethyl-2,6,10-dodecatrienyl ether(piperonyl farnesyl ether); and when R is an alicyclic alkyl group,3,4-methylenedioxybenyl cyclohexyl ether (piperonyl cyclohexyl ether),3,4-methylenedioxybenzyl 5-methyl-2-(1-methylethenyl)cyclohexyl ether(piperonyl isopulegyl ether), 3,4-methylenedioxybenzyl5-methyl-2-isopropylcyclohexyl ether (piperonyl menthyl ether),3,4-methylenedioxybenzyl 1-methyl-4-isopropylcyclohexenyl ether(piperonyl terpinenyl ether), 3,4-methylenedioxybenzyl1-methyl-4-isopropylcyclohexyl ether (piperonyl dihydroterpinenylether), 3,4-methylenedioxybenzyl 1-methyl-4-isopropenyl-6ether(piperonyl carvenyl ether), 3,4-cyclohexen-2-yl-methylenedioxybenzyl6-methyl-3-isopropenylcyclohexyl ether (piperonyl dihydrocarvenylether),3,4-methylenedioxybenzyl [1-(4-isopropenyl)cyclohexyl]methyl ether(piperonyl perillyl ether), 3,4-methylenedioxybenzyl4-methyl-1-isopropylbicyclo [3.1.0]hexan-4-yl ether (piperonyl4-thujanyl ether), 3,4-methylenedioxybenzyl 4-methyl-1-isopropylbicyclo[3.1.0]hexan-3-yl ether (piperonyl 3-thujanyl ether),3,4-methylenedioxybenzyl 6,6-dimethylbicyclo [3.1.1]hept-2-en-2-ethylether (piperonyl nopyl ether), 3,4-methylenedioxybenzyl1,3,3-trimethylbicyclo [2.2.1]heptan-2-yl ether (piperonyl fenchonylether) and 3,4-methylenedioxybenzyl endo-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl ether (piperonyl bornyl ether).

Of the piperonyl alcohol derivatives represented by the general formula(1), contained in the melanogenesis inhibitor of the present invention,a piperonyl alcohol derivative represented by the general formula (2)wherein R′ is an alicyclic alkyl group derived from a cyclic monoterpenealcohol, i.e. a residue obtained by removing a hydroxyl group from acyclic monoterpene alcohol, is a novel compound hitherto unknown, showsa striking melanogenesis-inhibiting property, and is safe and storable.

As specific examples of the piperonyl alcohol derivative represented bythe general formula (2), there can be mentioned 3,4-methylenedioxybenzyl5-methyl-2-(1cyclohexyl ether (piperonyl isopulegyl ether),-methylethenyl) 3,4-methylenedioxybenzyl 5-methyl-2-isopropylcyclohexylether (piperonyl menthyl ether), 3,4-methylenedioxybenzyl1-methyl-4-isopropylcyclohexenyl ether (piperonyl terpinenyl ether),3,4-methylenedioxybenzyl 1-methyl-4-isopropylcyclohexyl ether (piperonyldihydroterpinenyl ether), 3,4-methylenedioxybenzyl1-methyl-4-isopropenyl-6-cyclohexen-2-yl ether (piperonyl carvenylether), 3,4-methylenedioxybenzyl 6-methyl-3-isopropenylcyclohexenylether (piperonyl dihydrocarvenyl ether), 3,4-methylenedioxybenzyl[1-(4-isopropenyl)cyclohexyl]methyl ether (piperonyl perillyl ether),3,4-methylenedioxybenzyl 4-methyl-1-isopropylbicyclo[3.1.0]hexan-4-ylether (piperonyl 4-thujanyl ether), 3,4-methylenedioxybenzyl4-methyl-1-isopropylbicyclo [3.1.0]hexan-3-yl ether (piperonyl3-thujanyl ether), 3,4-methylenedioxybenzyl 6,6-dimethylbicyclo[3.1.1]hept-2-en-2-ethyl ether (piperonyl nopyl ether),3,4-methylenedioxybenzyl 1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl ether(piperonyl fenchonyl ether) and 3,4-methylenedioxybenzylendo-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl ether (piperonyl norbonylether). In particular, 3,4-methylenedioxybenzyl5-5-methyl-2-isopropylcyclohexyl ether (piperonyl menthyl ether) ispreferred.

Each compound of the present invention represented by the generalformula (1) or (2) can be synthesized by, for example, the followingmethod. That is, the compound can be produced, for example, by reducing3,4-methylenedioxybenzaldehyde (heliotropin) (easily obtainable as acommercial product) using hydrogen catalytically in the presence of anoble metal (e.g. Raney nickel) catalyst or using a metal hydride (e.g.sodium boron hydride) to convert it into 3,4-methylenedioxybenzylalcohol, reacting the alcohol with a hydrogen halide to convert it intoa 3,4-methylenedioxybenzyl halide, and then reacting the halide with analkoxide (produced from a hydroxy hydrocarbon) in the presence of abase, or converting the 3,4-methylenedioxybenzyl alcohol into3,4-methylenedioxybenzyl alkoxide in the presence of a base and thenreacting the alkoxide with a halogenated hydrocarbon group.

The skin preparation of the present invention refers to a preparationapplied to pellide (including scalp) as a cosmetic, a drug or a quasidrug. It can be used in various forms such as facial or skin carecosmetic (e.g. cream, lotion, emulsion, pack and fair skin lotion),make-up or body cosmetic (e.g. foundation, lipstick and eye shadow),aromatic cosmetic, scalp and hair cosmetic, wash, jelly, ointment andthe like.

The skin preparation of the present invention contains at least one kindselected from the piperonyl alcohol derivatives represented by thegeneral formula (1), i.e. the melanogenesis inhibitors of the presentinvention. The concentration of the melanogenesis inhibitor can bevaried appropriately depending upon the kind of base material, thecombination use of other melanogenesis inhibitor, the purpose ofapplication, etc., but ordinarily is preferably 0.001 to 20.0% by mass,more preferably 0.005 to 10.0% by mass relative to the total of thepreparation containing the inhibitor. Incidentally, as the othermelanogenesis inhibitor, there can be mentioned, for example, L-ascorbicacid and it derivatives, hydroquinone and its derivatives, kojic acid,linoleic acid (ester), lactic acid (ester) and placenta extract.

In the skin preparation of the present invention, there can be usedappropriately as necessary, in addition to at least one kind selectedfrom the above-mentioned melanogenesis inhibitors as an essentialcomponent, other components ordinarily used in skin preparations (e.g.cosmetics and drugs), such as powder component, oil and fat, wax,hydrocarbon oil, higher fatty acid, higher alcohol, synthetic ester oil,silicone, anionic surfactant, cationic surfactant, amphotericsurfactant, nonionic surfactant, humectant, water-soluble high-molecularcompound, thickening agent, film-making agent, ultraviolet absorber,sequestering agent, lower alcohol, polyhydric alcohol, saccharide, aminoacid derivative, organic amine, synthetic resin emulsion, pH-adjustingagent, skin nutrient, vitamin, anti-oxidant, anti-oxidizing aid, perfumeand water.

Specific examples of usable components are listed below. The skinpreparation of the present invention can be produced by compounding atleast one kind selected from these components together with theabove-mentioned essential component and employing an ordinary method.

As the powder component, there can be mentioned, for example, inorganicwhite pigments such as talc, kaolin, mica, magnesium carbonate, calciumcarbonate, aluminum silicate, barium silicate, calcium silicate,magnesium silicate, strontium silicate, metal tungstate, magnesium,silica, zeolite, barium sulfate, calcined calcium sulfate (calcinedgypsum), calcium phosphate, hydroxyapatite, ceramic powder, metal soap(zinc myristate, calcium palmitate, aluminum stearate), polyamide resinpowder (nylon powder), polyethylene powder, polymethyl methacrylatepowder, polystyrene powder, styrene/acrylic acid copolymer resin powder,organic powder (e.g. cellulose powder), titanium dioxide, zinc oxide andthe like; inorganic red pigments such as iron oxide (red iron oxide),iron titanate and the like; inorganic violet pigments such as carbonblack, Congo Violet, cobalt violet and the like; inorganic greenpigments such as cobalt titanate and the like; inorganic blue pigmentssuch as ultramarine, prussian blue and the like; pearl pigments such astitanium oxide-coated mica, titanium oxide-coated bismuth oxychloride,titanium oxide-coated talc, colored titanium oxide-coated mica, bismuthoxychloride, fish scale leaves and the like; metal powder pigments suchas aluminum powder, copper powder and the like; organic pigments such asRed 201, Red 202, Red 204, Red 205, Red 220, Red 226, Red 228, Red 405,Orange 203, Orange 204, Yellow 205, Yellow 401, Blue 404 and the like;organic pigments of, for example, zirconium, barium or aluminum lake,such as Red 3, Red 104, Red 106, Red 227, Red 230, Red 401, Red 505,Orange 205, yellow 4, Yellow 5, Yellow 202, Yellow 203, Green 3, Blue 1and the like; and natural coloring matter such as chlorophyll,β-carotene and the like. The powder component may be any as long as itis applicable to ordinary cosmetics. It is not restricted to thosementioned above.

As the liquid oil and fat, there can be mentioned, for example, avocadooil, tsubaki oil, turtle oil, macadamia nut oil, corn oil, mink oil,olive oil, rape seed oil, yolk oil, sesame oil, wheat germ oil, castoroil, linseed oil, safflower oil, cotton seed oil, soybean oil, peanutoil, tea seed oil, rice bran oil, jojoba oil, germ oil, triglycerine,trioctanoic acid glyceride and triisopalmitic acid glyceride.

As the solid oil and fat, there can be mentioned, for example, cacaofat, coconut oil, horse oil, hardened coconut oil, palm oil, beeftallow, sheep fat, hardened beef tallow, palm kernel oil, lard, beefbone fat, Japan wax kernel oil, hardened oil, beef foot oil, Japan waxand hardened castor oil.

As the wax, there can be mentioned, for example, bees wax, candelillawax, cotton wax, carnauba wax, bayberry wax, insect wax, spermaceti,lanolin, lanolin acetate, liquid lanolin, isopropyl ester of lanolinfatty acid, hexyl laurate, reduced lanolin, jojoba wax, hard lanolin,POE (polyoxyethylene) lanolin alcohol ether, POE lanolin alcoholacetate, POE cholesterol ether, polyethylene glycol ester of lanolinfatty acid and POE hydrogenated lanolin alcohol ether.

As the hydrocarbon oil, there can be mentioned, for example, liquidparaffin, squalene, paraffin and vaseline.

As the higher fatty acid, there can be mentioned, for example, lauricacid, myristic acid, palmitic acid, stearic acid, oleic acid,1,2-hydroxystearic acid, undecylenic acid, tall oil, isostearic acid,linolic acid, linolenic acid, eicosapentaenoic acid (EPA) anddocosahexaenoic acid (DHA).

As the higher alcohol, there can be mentioned, for example, straightchain alcohols such as lauryl alcohol, cetyl alcohol, stearyl alcohol,behenyl alcohol, myristyl alcohol, oleyl alcohol, cetostearyl alcoholand the like; and branched chain alcohols such as monostearyl glycerineether, 2-decyltetradecynol, lanolin alcohol, cholesterol, phytosterol,hexyldodecanol, isostearyl alcohol, octyldodecanol and the like.

As the synthetic ester oil, there can be mentioned, for example,isopropyl myristate, cetyl octanoate, octyl dodecyl myristate, isopropylpalmitate, butyl stearate, hexyl laurate, myristyl myristate, decyloleate, hexyl dodecyl dimethyloctanoate, cetyl lactate, myristyllactate, lanolin acetate, isocetyl stearate, isocetyl isostearate,cholesteryl 12-hydroxystearate, ethylene glycol di-2-ethylhexylate,dipentaerythritol-fatty acid ester, neopentyl glycol dicaprate,diisostearyl malate, glycerine di-2-heptylundecanoate,trimethylolpropane tri-2-ethylhexylate, trimethylolpropanetriisostearate, pentaerythritol tetra-2-ethylhexylate, glycerinetri-2-ethylhexylate, trimethylolpropane triisostearate, cetyl2-ethylhexanoate, 2-ethylhexyl palmitate, glycerine trimyristate,tri-2-heptylundecanoic acid glyceride, methyl ester of castor oil fattyacid, oleic acid oil, setostearyl alcohol, 2-heptylundecyl palmitate,diisobutyl adipate, 2-octyldodecyl N-layroyl-L-glutamate,di-2-heptylundecyl adipate, ethyl laurate, 2-hexyldecyl myristate,2-hexyldecyl palmitate, 2-heyldecyl adipate, diisopropyl sebacate,2-ethylhexyl succinate, ethyl acetate, butyl acetate, amyl acetate andtriethyl citrate.

As the silicone, there can be mentioned, for example, chainpolysiloxanes such as dimethylpolysiloxane, methylphenylpolysiloxane,methylhydrogenpolysiloxane and the like; alicyclic polysiloxanes such asdecamethylpolysiloxane, dodecamethylpolysiloxane,tetramethyltetrahydrogen-polysiloxane and the like; silicone resinshaving a three-dimensional network; and silicone rubber.

As the anionic surfactant, there can be mentioned, for example, fattyacid soaps such as soap base, sodium laurate, sodium palmitate and thelike; salts of higher alkyl sulfates such as sodium lauryl sulfate,potassium lauryl sulfate and the like; salts of alkyl ether sulfatessuch as triethanolamine POE lauryl sulfate, sodium POE lauryl sulfateand the like; salts of N-acyl sarcosinate such as sodium lauroylsarcosinate and the like; salts of higher fatty acid amide sulfonatessuch as sodium N-myristoyl-N-methyltaurinate, sodium coconut oil fattyacid methyl taurate, sodium lauryl methyl taurate and the like; salts ofphosphoric acid esters such as sodium POE oleyl ether phosphate, POEstearyl ether phosphate and the like; sulfosuccinic acid salts such assodium di-2-ethylhexylsulfosuccinate, sodium monolauroylmonoethanolamide polyoxyethylene sulfosuccinate, sodium lauryl polypropylene glycolsulfosuccinate and the like; alkylbenzenesulfonic acid salts such assodium linear dodecylbenzenesulfonate, triethanolamine lineardodecylbenzenesulfonate, linear dodecylbenzenesulfonic acid and thelike; N-acylglutamic acid salts such as monosodium N-lauroylglutamate,disodium N-stearoylglutamate, monosodium N-myristoyl-L-glutamate and thelike; salts of higher fatty acid ester sulfates such as sodium hardenedcocoyl glyceride sulfate and the like; sulfated oils such as Turkey redoil and the like; POE alkyl ether carboxylates; salts of POE alkyl allylether carboxylates; α-olefinsulfonic acid salts; salts of higher fattyacid ester sulfonates; salts of secondary alcohol sulfates; salts ofhigher fatty acid alkylol amide sulfates; sodium lauroyl monoethanolamide succinate; ditriethanolamine N-palmitoylasparatate; and sodiumcaseinate.

As the cationic surfactant, there can be mentioned, for example,alkyltrimethylammonium salts such as stearyltrimethylammonium chloride,lauryltrimethylammonium chloride and the like; dialkyldimethylammoniumsalts such as distearyldimethylammonium chloride and the like;alkylpyridinium salts such aspoly(N,N′-dimethyl-3,5-methylenepiperidinium) chloride, cetylpyridiniumchloride and the like; alkyl quaternary ammonium salts;alkyldimethylbenzylammonium salts; alkylisoquinolinium salts;dialkylmorpholinium salts; POE alkylamines; alkylamine salts; polyaminefatty acid ester derivatives; amyl alcohol fatty acid ester derivatives;benzalkonium chloride; and benzethonium chloride.

As the amphoteric surfactant, there can be mentioned, for example,imidazoline type amphoteric surfactants such as sodium salt of2-undecyl-N,N,N-(hydroxyethylcarboxymethyl)-2-imidazoline, disodium saltof 2-cocoyl-2-imidazolinium hydroxide-1-carboxyethyloxy and the like;and betaine type surfactants such as2-heptadecyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine,lauryldimethylaminoacetic acid betaine, alkylbetaines, amidobetaine,sulfobetaine and the like.

As the lipophilic nonionic surfactant, there can be mentioned, forexample, sorbitan-fatty acid esters such as sorbitan mono-oleate,sorbitan mono-isostearate, sorbitan mono-laurate, sorbitanmono-palmitate, sorbitan mono-stearate, sorbitan sesqui-oleate, sorbitantri-oleate, di-glycerol sorbitan penta-2-ethylhexylate, di-glycerolsorbitan tetra-2-ethylhexylate and the like; glycerinepolyglycerine-fatty acid esters such as mono-cotton seed oil fatty acidglyceride, mono-erucic acid glyceride, sesqui-oleic acid glyceride,mono-stearic acid glyceride, α, α′-oleic acid pyroglutamic acidglyceride, mono-stearic acid malic acid glyceride and the like;propylene glycol-fatty acid esters such as propylene glycol monostearateand the like; hardened castor oil derivatives; and glycerine alkylethers.

As the hydrophilic nonionic surfactant, there can be mentioned, forexample, POE sorbitan-fatty acid esters such as POE sorbitanmono-oleate, POE sorbitan mono-stearate, POE sorbitan mono-oleate, POEsorbitan tetra-oleate and the like; POE sorbit-fatty acid esters such asPOE sorbit mono-laurate, POE sorbit mono-oleate, POE sorbitpenta-oleate, POE sorbit mono-stearate and the like; POE glycerine-fattyacid esters such as POE glycerine mono-stearate, POE glycerinemono-isostearate, POE glycerine tri-isostearate and the like; POE-fattyacid esters such as POE mono-oleate, POE di-stearate, POEmono-di-oleate, ethylene glycol di-stearate and the like; POE alkylethers such as POE lauryl ether, POE oleyl ether, POE stearyl ether, POEbehenyl ether, POE 2-octyldodecyl ether, POE cholestanol ether and thelike; POE alkylphenyl ethers such as POE octylphenyl ether, POEnonylphenyl ether, POE di-nonylphenyl ether and the like; bururo nickssuch as bururo nick and the like; POE POP alkyl ethers such as POE POPcetyl ether, POE POP 2-decyl tetra-decyl ether, POE POP monobutyl ether,POE POP hydrogenated lanolin, POE POP glycerine ether and the like;tetra-POP tetra-POP ethylenediamine condensates such as tetronics andthe like; POE castor oil hardened castor oil derivatives such as POEcastor oil, POE hardened castor oil, POE hardened castor oilmono-isostearate, POE hardened castor oil tri-isostearate, POE hardenedcastor oil mono-pyroglutamic acid mono-isostearic acid diester, POEhardened castor oil maleic acid and the like; POE bees wax lanolinderivatives such as POE sorbit bees wax and the like; alkanol amidessuch as coconut oil fatty acid diethanol amide, lauric acid mono-ethanolamide, fatty acid isopropanol amide and the like; POE propyleneglycol-fatty acid ester; POE alkylamine; POE fatty acid amide;sucrose-fatty acid ester; POE nonylphenyl formaldehyde condensate;alkylethoxydimethylamine oxides; and tri-oleyl phosphate.

As the humectant, there can be mentioned, for example, polyethyleneglycol, propylene glycol, glycerine, 1,3-butylene glycol, xylitol,sorbitol, maltitol, chondoroitin sulfate, hyarulonic acid, mucoitinsulfate, cholesteryl 12-hydroxystearate, ceramide, glycosylceramide,sodium lactate, bile acid salt, dl-pyrrolidonecarboxylic acid salt,short chain soluble collagen, di-glycerine (EO) PO adduct, rosaroxburghil extract, extract of Achillea millefolium L., melilot extract.

As the natural water-soluble high-molecular compound, there can bementioned, for example, plant-based high-molecular compounds such as gumarabic, tragacanth gum, galactan, carob gum, karaya gum, carrageenan,pectin, agar, quince seed, algae colloid (brown algae extract), starch(rice, corn, potato, wheat), glycyrrhizic acid and the like;microorganism-based high-molecular compounds such as xanthane gum,dexstran, succinoglucan, pullulan and the like; and animal-basedhigh-molecular compounds such as collagen, casein, albumin, gelatin andthe like.

As the semi-synthetic water-soluble high-molecular compound, there canbe mentioned, for example, starch type high-molecular compounds such ascarboxymethyl starch, methylhydroxypropyl starch and the like; cellulosetype high-molecular compounds such as methyl cellulose, nitrocellulose,ethyl cellulose, methylhydroxypropyl cellulose, hydroxyethyl cellulose,sodium cellulose sulfate, hydroxypropyl cellulose, sodium carboxymethylcellulose (CMC), crystalline cellulose, cellulose powder and the like;and alginic acid type high-molecular compounds such as sodium alginate,alginic acid-propylene glycol ester and the like the syntheticwater-soluble high-molecular compound, there can be mentioned, forexample, vinyl type high-molecular compounds such as polyvinyl alcohol,polyvinyl methyl ether, polyvinylpyrrolidone, carboxyvinyl polymer(carbopol) and the like; polyoxyethylene type high-molecular compoundssuch as polyoxyethylene glycol 20,000, 4,000,000 or 600,000 and thelike; copolymer type high-molecular compounds such as polyoxyethylenepolyoxypropylene copolymer and the like; acrylic type high-molecularcompounds such as sodium polyacrylate, polyethyl acrylate,polyacrylamide and the like; polyethyleneimine; and cation polymers.

As the inorganic water-soluble high-molecular compound, there can bementioned, for example, bentonite, aluminum magnesium silicate (veegum),laponite, hectorite, silicic acid anhydride and the like.

As the thickening agent, there can be mentioned, for example, gumarabic, carrageenan, karaya gum, tragacanth gum, carob gum, quince seed,casein, dextrin, gelatin, sodium pectate, sodium arachate, methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, sodium polyacrylate, carboxyvinyl polymer, cellulosedialkyldimethylammonium sulfate, xanthane gum, aluminum magnesiumsilicate and bentonite.

As the ultraviolet absorber, there can be mentioned, for example,benzoic acid type ultraviolet absorbers such as p-aminobenzoic acid(hereinafter abbreviated as PABA), PABA/mono-glycerine ester,N,N-dipropoxyPABA/ethyl ester, N,N-diethoxyPABA/ethyl ester,N,N-dimethylPABA/ethyl ester, N,N-dimethylPABA/butyl ester,N,N-dimethylPABA/octyl ester and the like; anthranilic acid typeultraviolet absorbers such as homomenthyl N-acetylanthranilate and thelike; salicylic acid type ultraviolet absorbers such as amyl salicilate,menthyl salicilate, homomenthyl salicilate, octyl salicilate, phenylsalicilate, benzyl salicilate, p-isopropanol phenyl salicilate and thelike; cinnamic acid type ultraviolet absorbers such as octyl cinnamate,ethyl 4-isopropylcinnamate, methyl 2,5-diisopropylcinnamate, ethyl2,4-diisopropylcinnamate, methyl 2,4-diisopropylcinnamate, propylp-methoxycinnamate, isopropyl p-methoxycinnamate, isoamylp-methoxycinnamate, octyl p-methoxycinnamate (2-ethylhexylp-methoxycinnamate), 2-ethoxyethyl p-methoxycinnamate, cyclohexylp-methoxycinnamate, ethyl α-cyano-β-phenylcinnamate, 2-ethylhexylα-cyano-β-phenylcinnamate, glycerylmono-2-ethylhexanoyl-di-p-methoxycinnamate and the like; benzophenonetype ultraviolet absorbers such as 2,4-dihydroxybenzophenone,2,2′-dihydroxy-4-methoxybenzophenone,2,2′-dihydroxy-4,4′-dimethoxybenzophenone,2,2′,4,4′-tetrahydroxybenzophenone, 2-hydroxy-4-methoxybenzophenone,2-hydroxy-4-methoxy-4′-methylbenzophenone,2-hydroxy-4-methoxybenzophenone-5-sulfonic acid salt,4-phenylbenzophenone, 2-ethylhexyl-4′-phenylbenzophenone-2-carboxylate,2-hydroxy-4-n-octoxybenzophenone, 4-hydroxy-3-carboxybenzophenone andthe like; 3-(4′-methylbenzylidene)-d,l-camphor;3-benzilidene-d,l-camphor; urocanic acid; ethyl urocanate;2-phenyl-5-methylbenzoxazole; 2,2′-hydroxy-5-methylphenylbenztriazole;2-(2′-hydroxy-5′-tert-octylphenyl)benztriazole;2-(2′-hydroxy-5′-methylphenyl)benztriazole; dibenzalazine;dianisoylmethane; 4-methoxy-4′-tert-butyldibenzoylmethane; and5-(3,3-dimethyl-2-norbornylidene)-3-pentan-2-one.

As the sequestering agent, there can be mentioned, for example,1-hydroxyethane-1,1-diphosphonic acid, tetra-sodium1-hydroxyethane-1,1-diphosphonate, di-sodium edetate, tri-sodiumedetate, tetra-sodium edetate, sodium citrate, sodium polyphosphate,sodium m-phosphate, gluconic acid, phosphoric acid, citric acid,ascorbic acid, succinic acid and edetic acid.

As the lower alcohol, there can be mentioned, for example, methanol,ethanol, propanol, isopropanol, isobutyl alcohol and tert-butyl alcohol.

As the poly-hydric alcohol, there can be mentioned, for example,di-hydric alcohols such as ethylene glycol, propylene glycol,tri-methylene glycol, 1,2-butylene glycol, 1,3-butylene glycol,tetra-methylene glycol, 2,3-butylene glycol, penta-methylene glycol,2-butene-1,4-diol, hexylene glycol, octylene glycol and the like;tri-hydric alcohols such as glycerine, trimethylolpropane,1,2,6-hexanetriol and the like; tetra-hydric alcohols such aspentaerythritol and the like; penta-hydric alcohols such as xylitol andthe like; hexa-hydric alcohols such as sorbitol, mannitol and the like;poly-hydric alcohol polymers such as diethylene glycol, dipropyleneglycol, triethylene glycol, polypropylene glycol, tetraethylene glycol,diglycerine, polyethylene glycol, triglycerine, tetraglycerine,polyglycerine and the like; di-hydric alcohol alkyl ethers such asethylene glycol monomethyl ether, ethylene glycol monoethyl ether,ethylene glycol monobutyl ether, ethylene glycol monophenyl ether,ethylene glycol monohexyl ether, ethylene glycol mono-2-methylhexylether, ethylene glycol isoamyl ether, ethylene glycol benzyl ether,ethylene glycol isopropyl ether, ethylene glycol dimethyl ether,ethylene glycol diethyl ether, ethylene glycol dibutyl ether and thelike; di-hydric alcohol alkyl diethers such as diethylene glycolmonomethyl ether, diethylene glycol monoethyl ether, diethylene glycolmonobutyl ether, diethylene glycol dimethyl ether, diethylene glycoldiethyl ether, diethylene glycol dibutyl ether, diethylene glycol methylethyl ether, triethylene glycol monomethyl ether, triethylene glycolmonoethyl ether, propylene glycol monomethyl ether, propylene glycolmonoethyl ether, propylene glycol monobutyl ether, propylene glycolisopropyl ether, dipropylene glycol methyl ether, dipropylene glycolethyl ether, dipropylene glycol butyl ether and the like; di-hydricalcohol ether esters such as ethylene glycol monomethyl ether acetate,ethylene glycol monoethyl ether acetate, ethylene glycol monobutyl etheracetate, ethylene glycol monophenyl ether acetate, ethylene glycoldiadipate, ethylene glycol disuccinate, diethylene glycol monoethylether acetate, diethylene glycol monobutyl ether acetate, propyleneglycol monomethyl ether acetate, propylene glycol monoethyl etheracetate, propylene glycol monopropyl ether acetate, propylene glycolmonophenyl ether acetate and the like; glycerine monoalkyl ethers suchas chimyl alcohol, selachyl alcohol, batyl alcohol and the like;sugaralcohols such as sorbitol, maltitol, maltotriose, manitol, sucrose,erythritol, glucose, fructose, starch-decomposed sugar, maltose,xylitol, alcohol obtained by reduction of starch-decomposed sugar andthe like; grisoride; tetrahydrofurfuryl alcohol; POE tetrahydrofurfurylalcohol; POP butyl ether; POP POE butyl ether; tripolyoxypropyleneglycerine ether; POP glycerine ether; POP glycerine ether phosphate; andPOP POE pentaerythritol ether.

As the monosaccharide, there can be mentioned, for example, trioses suchas D-glycerylaldehyde, dihydroxyacetone and the like; tetroses such asD-erythrose, D-erythrulose, D-treose, erythritol and the like; pentosessuch as L-arabinose, D-xylose, L-lyxose, D-arabinose, D-ribose,D-ribulose, D-xylulose, L-xylulose and the like; hexoses such asD-glucose, D-talose, D-psicose, D-galactose, D-fructose, L-galactose,L-mannose, D-tagatose and the like; heptoses such as aldoheptose,heptulose and the like; octoses such as octulose and the like;deoxysugars such as 2-deoxy-D-ribose, 6-deoxy-L-galactose,6-deoxy-L-mannose and the like; amino sugars such as D-glucosamine,D-galactosamine, sialic acid, aminouronic acid, muramic acid and thelike; uronic acids such as D-glucuronic acid, D-mannuronic acid,L-guluronic acid, D-galacturonic acid, D-iduronic acid and the like.

As the oligosaccharide, there can be mentioned, for example, sucrose,gentianose, umbelliferose, lactose, planteose, iso-maltose, α,α-trehalose, raffinose, maltose, sorbitol, stachose and verbascose.

As the polysaccharide, there can be mentioned, for example, cellulose,quince seed, chondroitin sulfate, starch, galactan, starch sulfate,glycogen, gum arabic, heparan sulfate, hyaluronic acid, tragacanth gum,chondroitin, xanthane gum, mucoitin sulfate, guar gum, dexstran andcaronic acid.

As the amino acid, there can be mentioned, for example, neutral aminoacids such as glycine, alanine, valine, leucine, isoleucine, serine,threonine, tryptophane, cystine, systeine, methionine, proline,hydroxyproline and the like; acidic amino acids such as aspartic acid,glutamic acid, asparagine, glutamine and the like; and basic amino acidssuch as alginine, histidine, lysine, hydroxylysine and the like:

As the amino acid derivative, there can be mentioned, for example,sodium acylsarcosinate (sodium lauroylsarcosinate), acylglutamic acidsalt, sodium acyl-β-alaninate, glutathione and pyrrolidonecarboxylicacid.

As the organic amine, there can be mentioned, for example,monoethanolamine, diethanolamine, triethanolamine, morpholine,triisopropanolamine, 2-amino-2-methyl-1,3-propanediol and2-amino-2-methyl-1-propanol.

As the synthetic resin emulsion, there can be mentioned, for example,acrylic resin emulsion, polyethyl acrylate emulsion, acrylic resinsolution, polyalkyl acrylate emulsion and polyvinyl acetate resinemulsion.

As the pH-adjusting agent, there can be mentioned, for example, buffersolutions such as lactic acid-sodium lactate, citric acid-sodium citrateand the like.

As the vitamin, there can be mentioned, for example, vitamins A, B1, B2,B6 and E and their derivatives; pantothenic acid and its derivatives;and biotin.

As the anti-oxidant, there can be mentioned, for example, tocopherols,dibutylhydroxytoluene, butylhydroxyanisole and gallic acid esters.

As the anti-oxidizing aid, there can be mentioned, for example,phosphoric acid, citric acid, ascorbic acid, maleic acid, malonic acid,succinic acid, fumaric acid, cephalin, hexametaphosphate, phytic acidand ethylenediaminetetraacetic acid.

The skin preparation of the present invention can be made in variousforms such as solution, soluble form, emulsion, oil solution, gel,powder, water/oil two layers, water-oil-powder three layers and thelike. The essential component of the present invention is compoundedwith at least one kind selected from the above-mentioned components, andthe compound can be made into a form suitable for intended application,by an ordinary method.

The present invention is described in detail below by way of Examples.However, the present invention is in no way restricted to theseExamples.

The measuring apparatuses and measuring conditions used in the Examplesare shown below.

(1) Gas Chromatograph (G.C.)

-   -   Apparatus: HP-5890A (produced by Hewlett Packard Co.)    -   Column: Neutrabond-1 (25 m×0.25 m) (produced by GL Sciences        Inc.)    -   Carrier gas: helium    -   Measurement temperature: 100 to 220° C. (temp. elevation rate:        4° C./min)        (2) Proton NMR Spectrum (¹H-NMR)    -   Apparatus: AM-400 (400 MHz) (produced by Bruker Corporation)    -   Internal standard substance: tetramethylsilane        (3) Mass Spectrum (MS)    -   Apparatus: M-80B mass spectrometer (ionization voltage: 20 eV)        (produced by Hitachi, Ltd.)

First, in-depth description is made on synthesis examples of thepiperonyl alcohol derivative of the present invention.

SYNTHESIS EXAMPLE 1 Synthesis of Piperonyl Alcohol

In a 500-ml autoclave were placed 90 g (0.60 mol) of heliotropin, 270 mlof 1-propanol and 3 g of a Raney nickel catalyst (Raney-Ni). Hydrogengas was filled therein up to 4 MPa. The autoclave contents were stirredat 90° C. for about 10 hours. The reaction mixture was filtered and thefiltrate was concentrated. The resulting residue was purified by silicagel column chromatography (hexane:ethyl acetate=20:1) to obtain 27.6 gof piperonyl alcohol as white crystals (yield: 30.3%, G.C. purity:98.4%)

m.p.: 49-51° C.

¹H-NMR (CDCl₃, δ ppm): 1.86 (s,1H), 4.56 (s,2H), 5.95 (s,2H), 6.77-6.79(m,2H), 6.85 (s,1H)

MS: 152 (M⁺), 135, 123, 105, 93, 77, 65, 51, 39, 29

SYNTHESIS EXAMPLE 2 Synthesis of piperonyl n-butyl ether

4 g of sodium hydride (60%) and 100 ml of tetrahydrofuran (THF) werestirred in a nitrogen stream. Thereto was dropwise added, in 30 minutes,15.2 g (0.1 mol) of piperonyl alcohol dissolved in 70 ml of THF,followed by stirring for 30 minutes. Thereto was dropwise added 13.7 g(0.1 mol) of 1-bromobutane dissolved in THF, followed by stirring for 12hours. The stirring was stopped and the reaction mixture wasconcentrated. The concentrate was dropped into an excess amount of a 2 Naqueous hydrochloric acid solution. Heptane was added thereto forextraction. The extract was washed with water until the washings becameneutral, and then concentrated. The concentrate was purified by silicagel column chromatography (hexane:ethyl acetate=30:1) to obtain 8.0 g ofpiperonyl butyl ether at a yield of 38.5% as a transparent oilysubstance.

¹H-NMR (CDCl₃, δ ppm): 0.91 (t,J-7.5 Hz,3H), 1.39 (m,2H), 1.59 (m,2H),3.44 (t,J=5.6 Hz, 2H), 4.39 (s,2H), 5.94 (s,2H), 6.77-6.79 (m,2H), 6.85(s,1H)

MS: 208 (M⁺), 151, 135, 123, 106, 93, 77, 65, 51, 41, 29

SYNTHESIS EXAMPLES 3 TO 9

Piperonyl alkyl ether compounds shown in Table 1, each having adifferent hydrocarbon group R in the general formula (1) were producedin the same manner as in Synthesis Examples 1 and 2. The G.C. puritiesof the individual compounds were as follows.

TABLE 1 Synthesis Example R (hydrocarbon group) G.C. purity 3 Methyl99.8% 4 Ethyl 99.7% 5 Propyl 99.8% 6 Isobutyl 97.2% 7 Isoamyl 98.3% 8Hexyl 99.7% 9 Octyl 99.8%

The analytical data of the compounds shown in Table 1 are given below.

Piperonyl methyl ether C₉H₁₀O₃

¹H-NMR (CDCl₃, δ ppm): 3.34 (s,3H), 4.34 (s,2H), 5.93 (s,2H), 6.77(t,2H), 6.83 (s,1H)

MS: 166 (M⁺), 150, 135, 121, 105, 93, 77, 65, 51, 28

Piperonyl ethyl ether C₁₀H₁₂O₃

¹H-NMR (CDCl₃, δ ppm): 1.23 (t,3H), 3.52 (m,2H), 4.40 (s,2H), 5.94(s,2H), 6.78 (m,2H), 6.86 (d,1H)

MS: 180 (M⁺), 151, 135, 123, 106, 93, 77, 65

Piperonyl n-propyl ether C₁₁H₁₄O₃

¹H-NMR (CDCl₃, 6 ppm): 0.93 (t,3H), 1.61 (m,2H), 3.40 (t,2H), 4.40(s,2H), 5.93 (s,2H), 6.77 (m,2H), 6.85 (m,1H)

MS: 194 (M⁺), 151, 135, 123, 106, 93, 77

Piperonyl isobutyl ether C₁₂H₁₆O₃

¹H-NMR (CDCl₃, δ ppm): 0.92 (d,6H), 1.89 (m,1H), 3.20 (d,2H), 4.39(s,2H), 5.94 (s,2H), 6.78 (m,2H), 6.85 (d,1H)

MS: 208 (M⁺), 151, 135, 123, 106, 77

Piperonyl isoamyl ether C₁₃H₁₈O₃

¹H-NMR (CDCl₃, δ ppm): 0.89 (m,6H), 1.51 (m,2H), 1.65 (m,1H), 3.46(t,2H), 4.38 (s,2H), 5.94 (s,2H), 6.78 (m,2H), 6.84 (s,1H)

MS: 222 (M⁺), 151, 135, 123, 106, 93, 77, 43

Piperonyl n-hexyl ether C₁₄H₂₀O₃

¹H-NMR (CDCl₃, δ ppm): 0.89 (t,3H), 1.30 (m,6H), 1.61 (m,2H), 3.43(t,2H), 4.38 (s,2H), 5.94 (s,2H), 6.78 (m,2H), 6.85 (t,1H)

MS: 236 (M⁺), 151, 135, 123, 106, 93, 77, 43

Piperonyl n-octyl ether C₁₆H₂₄O₃

¹H-NMR (CDCl₃, δ ppm): 0.88 (t,3H), 1.29 (m,10H), 1.58 (m,2H), 3.43(t,2H), 4.39 (s,2H), 5.93 (s,2H), 6.77 (m,2H), 6.85 (d,1H)

MS: 264 (M⁺), 151, 136, 123, 106, 93, 77, 57, 43

SYNTHESIS EXAMPLE 10 Synthesis of piperonyl 1-menthyl ether

In a 500-ml flask were placed 30 g (0.2 mol) of piperonyl alcohol, 102.8g (1.0 mol) of a 35% aqueous hydrochloric acid solution and 150 ml oftoluene. They were stirred in a nitrogen stream at 90° C. for about 2hours. The stirring was stopped and phase separation was made to removethe aqueous phase. The toluene phase was washed with water and anaqueous NaHCO₃ solution in this order, and then with water severaltimes. The toluene phase was concentrated under reduced pressure toobtain 32.28 g of piperonyl chloride. In a 500-ml flask were placed 8.4g (0.21 mol) of sodium hydride and 100 ml of toluene, and they werestirred under refluxing in a nitrogen stream, in a 120° C. oil bath.Thereto was dropwise added, in 20 minutes, 29.6 g (0.19 mol) of1-menthol dissolved in 30 ml of toluene. 30 minutes later, 32.3 g (0.19mol) of the piperonyl chloride dissolved in 32 ml of toluene was addeddropwise, followed by stirring for about 1 hour. The stirring wasstopped and 110 ml of a 2 N aqueous hydrochloric acid solution was addedto terminate a reaction, after which phase separation was made. Thetoluene phase was washed with water three times and then concentrated.The resulting concentrate was distilled for purification to obtain 35.6g (yield: 30.6%, purity: 97.2%) of piperonyl 1-mentyl ether as atransparent oily substance.

b.p.: 169° C./200 Pa

¹H-NMR (CDCl₃, 6 ppm): 0.72 (d,3H), 0.89 (m,9H), 1.27 (m,2H), 1.64(m,2H), 2.17 (m,1H), 2.28 (m,1H), 3.15 (m,1H), 4.31 (d,1H), 4.53 (d,1H),5.93 (s,2H), 6.78 (m,2H), 6.85 (s,1H)

COMPARATIVE SYNTHESIS EXAMPLE 1 Synthesis of vanillyl ethers

Various vanillyl alcohols were produced in the same manner as inSynthesis Example 1 except that vanillin (X=OH, Y=OMe) or ethylvanillin(X=OH, Y=OEt) was used in place of the heliotropin used in SynthesisExample 1. Using these vanillyl alcohols, vanillyl ethers havingdifferent substituents R₁ were produced according to the methoddescribed in JP-A-57-9729. Also, 3,4-dimethoxybenzyl alcohol wasproduced in the same manner as in Synthesis Example 1 except thatmethylvanillin (X=Y=OMe) was used in place of the heliotropin used inSynthesis Example 1. Using this alcohol, vanillyl ethers havingdifferent substituents R₁ were produced in the same manner as inSynthesis Example 10.

COMPARATIVE SYNTHESIS EXAMPLE 2 Synthesis of piperonyl esters

The piperonyl alcohol produced in Synthesis Example 1 was reacted with acarboxylic acid anhydride or a carboxylic acid chloride in the presenceof a base. The reaction mixture was purified with distilled water or bysilica gel column chromatography to produce piperonyl esters havingdifferent substituents R₂.

COMPARATIVE SYNTHESIS EXAMPLE 3 Synthesis of piperonyl amines

A Schiff base obtained from heliotropin and an alkyl amine washydrogenated in the presence of 5% Pd—C to produce piperonyl amineshaving different substituents R₃.

EXAMPLE 1 Melanogenesis Inhibition Test and Cytotoxicity Test

The following tests a) and b) were conducted on the compounds shown inSynthesis Examples and Comparative Synthesis Examples to examine theirmelanogenesis-inhibiting effects.

-   -   a) Cytotoxicity test (using B16 melonoma cells)    -   b) Melanogenesis inhibition test (visual evaluation) (using B16        melonoma cells)        Evaluation Methods

8×10⁴ B16 melanoma cells were inoculated in a plastic-made culture flask(25 cm²). The cells were cultured in a 10% serum-containing DMEN medium(produced by Nissui Pharmaceutical co., Ltd., trade name) in thepresence of 5% carbon dioxide at 37° C. 3 days later, a test samplediluted with ethanol was added thereto, and culture was conducted for 3days. After the completion of the culture, the medium was removed andthe flask contents were washed with a phosphate buffer solution(hereinafter referred t as PBS). The cells were peeled from the flaskinner wall using a medium containing trypsin and EDTA(ethylenediaminetetraacetic acid). The resulting cells suspension wascentrifuged to recover cells. Part of the cells was taken and the numberof cells was measured using a Coulter counter. The concentration atwhich the number of cells became 95 to 100 (when the number of cells inthe case of using test sample-free ethanol (solvent) was taken as 100)was taken as a concentration giving no cytotoxicity. A melanogenesisinhibition test was carried out in this concentration range. The cellsobtained were washed once with PBS and then the whiteness of theprecipitate was rated visually based on the following evaluationstandard.

Evaluation Standard

-   -   −: Same as the solvent control (black)    -   +−: Slightly different from the solvent control (black-gray)    -   +: Clearly different from the solvent control (gray)    -   ++: Coloring of cells is very low (gray-white)    -   +++: No coloring of cells (white)

The results are shown in Tables 2, 3, 4 and 5.

TABLE 2 Synthesis Concentration (μg/ml) Example R = 12.5 6.3 3.1 Example5 Propyl + N.T. N.T. 2 Butyl ++ N.T. N.T. 6 Isobutyl ++ N.T. N.T. 7Isoamyl ++ N.T. N.T. 8 Hexyl ++ N.T. N.T. 9 Octyl + + N.T. 10 1-Mentyl+++ ++ + Comparative 3 Methyl − N.T. N.T. Example 4 Ethyl − N.T. N.T.N.T.: not tested

As is clear from Table 2, the compounds whose R is 3 or more carbonatoms, showed an effect and 1-menthyl ether showed a particularlysuperior fair skin effect.

TABLE 3 Concentration (μg/ml) Synthesis Example R₂ = 12.5 ComparativeComparative Example 2 Butyl — Example Comparative Example 2 Hexyl —(piperonyl Comparative Example 2 Octyl — ester) Comparative Example 2Dodecyl —

TABLE 4 Concentration (μg/ml) Synthesis Example R₃ = 12.5 ComparativeComparative Example 3 Butyl — Example Comparative Example 3 Hexyl —(piperonyl Comparative Example 3 Octyl — amine) Comparative Example 3Dodecyl —

As is clear from Table 3 and Table 4, the piperonyl amines and thepiperonyl esters showed no melanogenesis hindrance effect and it wasconfirmed that melanogenesis inhibition is an effect unique to thecompound of the present invention.

TABLE 5 Concentration (μg/ml) X Y R₁ 12.5 Synthesis Example 2 X, Y =OCH₂O Butyl ++ Comparative Synthesis OH OMe Methyl − Example 1Comparative Synthesis OH OEt Methyl − Example 1 Comparative Synthesis OHOEt Ethyl − Example 1 Comparative Synthesis OH OEt Butyl +− Example 1Comparative Synthesis OH OMe Butyl +− Example 1 Comparative SynthesisOMe OMe Butyl − Example 1

As is clear from Table 5, the melanogenesis inhibitor of the presentinvention containing the piperonyl alcohol having a methylendioxy groupas an aromatic ring substituent showed the highest melanogensis hindraceeffect.

EXAMPLE 2 Mechanism for Melanogenesis Hindrance

A tyrosinase activity hindrance test and a tyrosinase biosynthesishindrance test were conducted according to the following test methods toexamine the mechanism for hindrance of melanin denovo synthesis. Kojicacid hitherto used widely as a fair skin preparation was used as acontrol.

Test Method for Tyrosinase Activity Hindrance

100 μl of a suspension containing 5×10⁵/ml of B16 melanoma cells wasinoculated into a 96-well plate, and culture was made at 37° C.overnight in 5% CO₂. Next day, the culture medium was removed and 90 μlof 1% Triton X100 was added. The resulting mixture was allowed to standat room temperature for 1 hour. Then, the plate was shaken gently, afterwhich there were added 90 μl of 1% DOPA and 20 μl of a sample dilutedwith ethanol to a given concentration. Immediately, measurement was madeat 450 nm and the value obtained was taken as a measured value of 0hour. Thereafter, the plate was transferred into a 37° C. incubator togive rise to a reaction for 1 to 3 hours. During the period, measurementwas made at intervals of 1 hour. The activity hindrance effect of thesample was determined as a proportion to the melanin amount when nosample was added.

Test Method for Tyrosinase Biosynthesis Hindrance

In this method, tyrosinase biosynthesis hindrance is indicatedindirectly by measuring intra-cell tyrosinase activity.

100 μl of a suspension containing 3×10⁵/ml of B16 melanoma cells wasinoculated into a 96-well plate, and culture was made at 37° C.overnight in 5% CO₂. Next day, the medium was changed with 200 μl of asample-containing culture medium, and culture was made for 2 days underthe same conditions. Thereafter, the supernatant liquid was removed andthe residue was washed with 200 μl of a phosphate buffer solution twice.Then, 100 μl of 1% Triton X100 was added and the mixture was allowed tostand at room temperature for 1 hour, followed by gentle shaking. Next,100 μl of 1% DOPA was added. Measurement was made in the same manner asin the above test method for tyrosinase activity hindrance.Incidentally, in this test, two same plates were prepared and one ofthem was used for measurement by MTT method in order to prove that therewas no cytotoxicity.

The results are shown in Tables 6 to 8.

TABLE 6 Tyrosinase biosynthesis hindrance of piperonyl 1-menthyl etherConcentration Hindrance % Cell propagation rate % 12.5 ppm  80.0 91.06.3 ppm 63.0 98.8 3.1 ppm 48.0 104.7

TABLE 7 Tyrosinase activity hindrance of kojic acid ConcentrationHindrance % 200 ppm 59.8 100 ppm 33.0  50 ppm 21.4

TABLE 8 Tyrosinase biosynthesis hindrance of kojic acid ConcentrationHindrance % Cell propagation rate % 200 ppm 21.0 96.2 100 ppm 21.0 97.3 50 ppm 21.0 100.8

As is clear from Table 6, piperonyl 1-menthyl ether exhibited atyrosinase biosynthesis hindrance effect concentration-dependently atconcentrations of no cytotoxicity. Incidentally, there was no tyrosinaseactivity hindrance effect. Meanwhile, as is clear from Tables 7 and 8,kojic acid hindered tyrosinase activity concentration-dependently. Fromthis result, it was confirmed that the melanogenesis inhibitor of thepresent invention does not hinder tyrosinase activity, but hinderstyrosinase biosynthesis and shows a novel melanogenesis-hinderingactivity and that this activity is 10 times or more the activity ofkojic acid.

EXAMPLE 3 Safety Test

On piperonyl 1-menthyl ether were carried out a skin sensitization test,a skin irritation test and a phototoxicity test to examine the safety ofthe compound. The results are shown in Table 9.

TABLE 9 Safety test of piperonyl 1-menthyl ether skin irritationNegative (1%, open coating to guinea pig) skin sensitization Negative(1%, guinea pig maximization) Phototoxicity Negative (1%, UV applicationto guinea pig)

In all tests, the results were negative at a concentration of 1%, and itwas confirmed that the melanogenesis inhibitor of the present inventionis highly safe.

EXAMPLE 4

A cream having the following composition was produced by an ordinarymethod.

Stearic acid 6.0% by mass Sorbitan monostearate 2.0% by massPolyoxyethylene (20 moles) sorbitan 1.5% by mass mono-stearate Propyleneglycol 10.0% by mass  Piperonyl 1-menthyl ether 7.0% by mass Glycerinetrioctanoate 10.0% by mass  Squalene 5.0% by mass Sodium hydrogensulfite0.01% by mass  Ethylparaben 0.3% by mass Perfume Appropriate Deionizedwater Residue

EXAMPLE 5

A cream having the following composition was produced by an ordinarymethod.

Stearyl alcohol 7.0% by mass Stearic acid 2.0% by mass Hydrogenatedlanolin 2.0% by mass Squalane 5.0% by mass 2-Octyldodecyl alcohol 6.0%by mass Polyoxyethylene (25 moles) 3.0% by mass cetyl alcohol etherGlycerine mono-stearate 2.0% by mass Propylene glycol 5.0% by massPiperonyl 1-menthyl ether 0.05% by mass  Perfume Appropriate Sodiumhydrogensulfite 0.03% by mass  Ethylparaben 0.3% by mass Deionized waterResidue

EXAMPLE 6

An emulsion having the following composition was produced by an ordinarymethod.

Stearic acid 2.5% by mass Cetyl alcohol 1.5% by mass Vaseline 5.0% bymass Liquid paraffin 10.0% by mass Polyoxyethylene (10 moles) mono-oleic2.0% by mass acid ester Polyethylene glycol 15 3.0% by massTriethanolamine 1.0% by mass Piperonyl 1-menthyl ether 10.0% by massSodium hydrogensulfite 0.01% by mass Ethylparaben 0.3% by massCarboxyvinyl polymer 0.05% by mass Perfume Appropriate Deionized waterResidue

EXAMPLE 7

An emulsion having the following composition was produced by an ordinarymethod.

(Oil phase) Stearyl alcohol 1.5% by mass Squalene 2.0% by mass Vaseline2.5% by mass Deodorized liquid lanolin 1.5% by mass Oenothera tetrapteraCav. oil 2.0% by mass Isopropyl myristate 5.0% by mass Glycerinemono-oleate 2.0% by mass Polyoxyethylene (60 moles) hardened castor oil2.0% by mass Tocopherol acetate 0.05% by mass Ethylparaben 0.2% by massButylparaben 0.1% by mass Piperonyl 1-menthyl ether 1.0% by mass Arbutin1.0% by mass Perfume Appropriate (Aqueous phase) Sodium hydrogensulfite0.01% by mass Glycerine 5.0% by mass Sodium hyaluronate 0.01% by massCarboxyvinyl polymer 0.2% by mass Potassium hydroxide 0.2% by massPurified water Residue

EXAMPLE 8

A jelly having the following composition was produced by an ordinarymethod.

95% ethyl alcohol 10.0% by mass Dipropylene glycol 15.0% by massPolyoxyethylene (50 moles) oleyl 2.0% by mass alcohol ether Carboxyvinylpolymer 1.0% by mass Sodium hydroxide 0.15% by mass L-alginine 0.1% bymass Piperonyl 1-menthyl ether 1.0% by mass Piperonyl n-butyl ether 1.0%by mass Methylparaben 0.2% by mass Perfume Appropriate Deionized waterResidue

EXAMPLE 9

A beauty lotion having the following composition was produced by anordinary method.

Ethanol (95%) 10.0% by mass Polyoxyethylene (20 moles) octyldodecanol1.0% by mass Methylparaben 0.15% by mass Pantothenol ethyl ether 0.1% bymass Piperonyl isoamyl ether 0.05% by mass Potassium hydroxide 0.1% bymass Glycerine 5.0% by mass Dipropylene glycol 10.0% by mass Sodiumhydrogensulfite 0.03% by mass Carboxyvinyl polymer 0.2% by mass Purifiedwater Residue

EXAMPLE 10

A pack having the following composition was produced by an ordinarymethod.

Dipropylene glycol 5.0% by mass Polyoxyethylene (60 moles) hardened 5.0%by mass castor oil Piperonyl lauryl ether 0.1% by mass Piperonyl1-menthyl ether 0.1% by mass Olive oil 5.0% by mass Tocopherol acetate0.2% by mass Ethylparaben 0.2% by mass Perfume 0.2% by mass Sodiumhydrogensulfite 0.03% by mass Polyvinyl alcohol (saponification degree:13.0% by mass 90, polymerization degree: 2000) Ethanol 7.0% by massPurified water Residue

EXAMPLE 11

An ointment having the following composition was produced by an ordinarymethod.

Polyoxyethylene (30 moles) cetyl ether 2.0% by mass Glycerinemono-stearate 10.0% by mass Liquid paraffin 10.0% by mass Vaseline 40.0%by mass Cetanol 6.0% by mass Methylparaben 0.1% by mass Butylparaben0.1% by mass Glycerine mono-stearate 2.0% by mass Piperonyl 1-menthylether 2.0% by mass Propylene glycol 10.0% by mass Deionized waterResidue Perfume Appropriate(Production)

Propylene glycol is added to deionized water, followed by heating toobtain a solution. The solution is kept at 70° C. (this becomes anaqueous phase). Other components are mixed at 70° C. to obtain asolution (this becomes an oil phase). The oil phase is added to theaqueous phase; the mixture is uniformly emulsified using a homomixer;the emulsion is cooled and then packed to obtain a product.

According to the present invention there are provided a novelmelanogenesis inhibitor which contains a piperonyl alcohol derivativeand which has an excellent melanogenesis-inhibiting effect; and a skinpreparation which contains the novel melanogenesis inhibitor and whichis highly stable and highly safe and has an excellent fair skin effect.

According to the present invention there is also provided a novelpiperonyl alcohol derivative which is included in the above-mentionedpiperonyl alcohol derivative and which is useful as a component of theabove novel melanogenesis inhibitor.

1. A melanogenesis inhibitor represented by the following formula:

wherein R is an alicyclic alkyl group derived from a cyclic monoterpenealcohol.
 2. A skin preparation characterized by containing amelanogenesis inhibitor of the formula set forth in claim
 1. 3. A skinpreparation characterized by containing 0.001 to 20.0% by mass of amelanogenesis inhibitor set forth in claim
 1. 4. A skin preparationaccording to claim 2, which has a form of cream, lotion, emulsion,jelly, beauty lotion, pack or ointment.
 5. A skin preparation accordingto claim 3, which has a form of cream, lotion, emulsion, jelly, beautylotion, pack or ointment.